We have developed an animal model of post-traumatic stress disorder (PTSD) based on the combination of inescapable cat exposure and social instability. This psychosocial stress manipulation produces PTSD-like sequelae in rats, including heightened anxiety, exaggerated startle, impaired memory, greater cardiovascular and hormonal reactivity to an acute stressor and an exaggerated response to the 12-adrenergic receptor antagonist, yohimbine. The proposed research will apply our PTSD model to study therapeutics which may block the development of PTSD-like sequelae, to understand the neurobiological basis of traumatic memory formation and retrieval and to examine the neuroendocrine mechanisms which underlie PTSD-like sequelae. The following three questions address the specific aims of this proposal. 1) Will pharmacological treatments which reduce glutamate and CRF activity block PTSD-like sequelae in rats? Research has demonstrated the involvement of glutamate and corticotropin-releasing factor (CRF) in traumatic memory formation and in the pathophysiology of PTSD. Pharmacotherapy that will target these two neuromodulatory systems has the potential to ameliorate the complex cluster of symptoms present in people with PTSD. We hypothesize that treatment with 1) Tianeptine, an antidepressant which stabilizes NMDA receptor currents;2) Lamotrigine, a Na+ channel blocker which reduces glutamate levels;or 3) a CRH-1 receptor antagonist, will block the development of PTSD-like sequelae in psychosocially stressed rats. 2) What are the mechanisms underlying the formation and persistence of traumatic memories? The hallmark feature of PTSD is the establishment and persistence of a pathologically intense memory of a traumatic event. We will examine molecular mechanisms involved in the formation and remote memory retrieval of the fear conditioning component of our PTSD model. Specifically, we will study the influence of predator-induced fear conditioning to activate molecular signalling molecules, including calcium/calmodulin- dependent kinase II (CaMKII) and cAMP-response element binding protein (CREB), in response to the traumatic experience and then, weeks later, to a reminder of that experience. Second, we will study epigenetic plasticity which may underlie the formation and long-term persistence of traumatic memories. Specifically, we will assess the effects of psychosocial stress on BDNF gene methylation in the hippocampus, amygdala and prefrontal cortex. 3) Does psychosocial stress in rats produce PTSD-like abnormalities in neuroendocrine activity? PTSD involves disturbances of neuroendocrine systems, including reduced basal glucocorticoid levels and increased glucocorticoid negative feedback sensitivity, as well as changes in CRF levels and glucocorticoid receptors. We will evaluate whether our psychosocial stress regimen produces a PTSD-like phenotype in corticosterone responses, glucocorticoid receptors and CRF levels in the hypothalmus, hippocampus and amygdala. Overall, the goal of these three complementary approaches is to use our animal model of PTSD to provide insight into the neuroendocrine and mechanistic features of PTSD and to develop more effective treatments of stress-induced anxiety and mood disorders. CLINICAL RELEVANCE: Veterans exposed to traumatic stress during combat have a high incidence of anxiety disorders, such as PTSD. We have yet to achieve a satisfactory understanding of the etiology of stress-induced sequelae and how to effectively treat stress-related mental disorders. This research will enhance our understanding of the neurobiology of traumatic memory processing and aid in the development of therapeutic treatments for PTSD. PUBLIC HEALTH RELEVANCE: Relevance of the Proposed Research to Veterans health Traumatic stress, which is commonly experienced during combat, can produce long-lasting emotional and mental disturbances, including depression and PTSD. Veterans with mood and anxiety disorders also have a high rate of hospitalization from secondary health-related problems, such as heart disease. Therefore, we need to conduct research to improve our understanding of the physiological basis of traumatic stress. To work toward achieving this goal the proposed research involves psychosocial stress in rats which produces PTSD-like responses at behavioral, pharmacological and physiological levels. This research will apply our established animal model of PTSD to improve our understanding of the neurobiological basis of the pathological effects of stress on brain and behavior to develop more effective pharmacotherapy for veterans with PTSD.